Methods of treating persistent impairment of consciousness by vagus nerve stimulation

ABSTRACT

Methods of treating persistent impairment of consciousness in humans and animals by vagus nerve stimulation are provided. These methods comprise selecting an appropriate human or animal subject and applying to the subject&#39;s vagus nerve an electrical stimulation signal having parameter values effective in modulating the electrical activity of the vagus nerve in a manner so as to modulate the activity of preselected portions of the brain.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional of pending U.S. patentapplication Ser. No. 09/613,368, filed Jul. 10, 2000, which is adivisional of U.S. patent application Ser. No. 08/866,800 (now U.S. Pat.No. 6,104,956), filed May 30,1997, which claims priority from U.S.Provisional Patent Application Serial No. 60/018,813, filed May 31,1996. The texts of U.S. patent application Ser. No. 09/613,368; U.S.patent application Ser. No. 08/866,800 and U.S. Provisional PatentApplication Serial No. 60/018,813 are hereby incorportated herein byreference in their entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to methods and apparatus formodulating neural plasticity in the nervous system. Neural plasticityincludes phenomena such as memory and learning consolidation processes,as well as recovery of function following traumatic brain injury. Themethods of the present invention are directed to modulating neuralplasticity, improving memory and learning consolidation processes,cognitive processing, and motor and perceptual skills in both normalsubjects and subjects suffering from chronic memory impairment,alleviating symptoms and improving outcome in subjects suffering fromtraumatic brain injury, preventing the development of epilepsy insubjects prone to developing this condition, and treating persistentimpairment of consciousness. These methods employ electrical stimulationof the vagus nerve in human or animal subjects via application ofmodulating electrical signals to the vagus nerve by use of aneurostimulating device.

BACKGROUND OF THE INVENTION

[0003] Vagal Afferents and their Influence on Physiology and Behavior

[0004] The vagus nerve comprises both somatic and visceral afferents(inward conducting nerve fibers that convey impulses toward a nervecenter such as the brain or spinal cord) and efferents (outwardconducting nerve fibers that convey impulses to an effector to stimulatethe same and produce activity). The vast majority of vagal nerve fibersare C fibers, and a majority are visceral afferents having cell bodieslying in masses or ganglia in the neck. For the most part, the centralprojections terminate in the nucleus of the solitary tract, which sendsfibers to various regions of the brain such as the hypothalamus,thalamus, and amygdala. Other projections continue to the medialreticular formation of the medulla, the cerebellum, the nucleuscuneatus, and other regions. The solitary nucleus has important pathwaysto brain regulatory networks, including the serotonergic nuclei and thenoradrenergic nuclei. These neurotransmitter systems are crucial formemory, learning, cognitive and sensory/perceptual processing, and motorskills. These neurotransmitters also prevent the development ofepilepsy, i.e., they are antiepileptogenic, and are important for theprocesses that subserve brain recovery following traumatic injury.

[0005] The majority of vagus nerve fibers are viscerosensory afferentsoriginating from receptors located in the lungs, aorta, heart, andgastrointestinal tract, and convey, among other things, cardiopulmonaryand nocicepive information to various forebrain and brainstem structures(Cechetto, D. F. (1987) Federation Proceedings 46:17-23). Threepopulations of vasal afferents are known to exist: the vastly abundantunmyelinated C fibers involved in pain mediation, and small myelinated Bfibers and large A fibers which subserve autonomic reflexes and probablymore complex visceroendocrine responses, such as glucose metabolism andfluid homeostasis (Barraco, I. R. A. (1994) Nucleus of the SolitaryTract, CRC Press, Boca Raton). Nearly all vagal afferents terminate inthe nucleus of the solitary tract (NTS), where the information theycarry is first integrated before being divergently projected to eachrostral level of the neuroaxis. Because NTS neurons impinge on a numberof CNS structures and regions, including the hypothalamus, hippocampus,amygdaloid complex, dorsal raphe nucleus, and mesencephalic reticularformation (Rutecki, P. (1990). Epilepsia 31 (Suppl. 2):51-56), anequally large number of cognitive, somatic, and visceral operations canbe initiated or coordinated with autonomic information. Thus, as onemight expect, neural signals sent via vagal afferents have a profoundimpact on CNS function that, in turn, influence general behaviors andarousal. For instance, electrical stimulation of the cervical vagus canmodify the electrophysiological profile of neocortical, thalamic, andcerebellar neurons. These and other changes in supramedullary circuitsare thought to precipitate overt changes in, for example, sleep, feedingbehavior, responsiveness to noxious stimuli, and monosynaptic muscularreflexes (Rutecki, supra).

[0006] Vagus Nerve Stimulation and the Brain

[0007] Vagus nerve stimulation has been shown to cause activation ofseveral parts of the brain that are specifically involved in cognitiveprocessing, memory, learning, sensory and motor processing, and affectsregions of the brain that are prone to developing epilepsy or whichregulate the development of epilepsy (Naritoku et al. (1995) In Ashleyet al., Eds., Traumatic Brain Injury Rehabilitation, CRC Press, BocaRaton, pp. 43-65). These studies demonstrate that vagus nervestimulation activates the amygdala and cingulate cortex, which areinvolved in learning and cognitive processing. Such stimulation alsoactivates several thalamic nuclei which serve relay functions. Inaddition, it activates several sensory nuclei, including the auditory,visual, and somatic sensory systems. Finally, vagus nerve stimulationactivates monoaminergic nuclei, especially the locus ceruleus and A5groups, which provide norepinephrine to the brain. Monoamines arecrucial for both learning and memory, and for preventing the developmentof epilepsy (Jobe et al. (1981) Biochem. Pharmacol. 30:3137-3144).

[0008] Modulation of Memory by Arousal

[0009] Both anecdotal and scientific reports have long suggested thatsome memories are remembered far more distinctly than others when thosememories were stored at the time of a significant emotional or stressfullife event. This appears to be an important memory mechanism by whichthe brain selectively enhances the storage and retrievability of moreimportant memories, while minimizing interference from those that arecomparatively inconsequential. The research to date indicates that thestorage of permanent memories is susceptible to enhancing or disruptinginfluences shortly after an initial exposure to salient information(McGaugh, J. L. (1989) Annual Review of Neuroscience 12:255-287;McGaugh, J. L. (1990) Psychological Science 1:15-25; Squire, L. R.(1987) Memory and Brain, Oxford University Press, New York). In clinicaland animal studies, improved retention can be produced by a wide varietyof treatments, including the peripheral administration of certainhormones, neuromodulators, and stimulant drugs, such as amphetamine. Onefactor which seems to be common to those agents that enhance memory isthat most are related in some way to arousal.

[0010] Arousal is associated with the release of adrenal catecholaminesand numerous other substances such as the pituitary hormones ACTH andvasopressin. Peripheral administration of these substances hasconsistently been shown to modulate memory in a dose- and time-dependentfashion (McGaugh et al. (1989) “Hormonal Modulation of Memory” In Brushet al., Eds., Psychoendocrinology, Academic Press, New York). Forinstance, when moderate doses of epinephrine or its agonists are givenshortly after training on a memory task, there is enhancement ofretention performance measured some time later (Gold et al. (1977)Behavioral Biology 20:197-207). Importantly, many substances thatmodulate memory when either endogenously released or deliveredsystemically do not freely cross the blood-brain barrier, and aretherefore unlikely to influence memory by direct pharmacological actionon the brain. Instead, they appear to activate peripheral receptors thatin turn send neural messages to those central nervous system (CNS)structures involved in memory consolidation.

[0011] Role of the Vagus Nerve in Mediating Arousal-induced MemoryModulation

[0012] The vagus nerve appears to be at least partially responsible forthe observed memory-modulating effects of peripherally-acting agents.Williams et al. ((1991) “Vagal afferents: A possible mechanism for themodulation of memory by peripherally acting agents” In: Frederickson etal., Eds., Neuronal control of bodily function, basic and clinicalaspects: Vol. 6., Peripheral signaling of the brain: Role inneuralimmune interactions, learning and memory, Hogrefe and Huber,Toronto, pp. 467-472) and Williams et al. ((1993) Physiology andBehavior 54:659-663) demonstrated that severing the vagus nerve belowthe level of the diaphragm attenuated the memory-enhancing effects of4-OH amphetamine, an amphetamine derivative that does not freely enterthe CNS, as well as the memory-impairing effects ofperipherally-administered Leu-enkephalin. Similar attenuation has alsobeen demonstrated with respect to the memory-modulating capacity ofcholecystokinin (Flood et al. (1987) Science 234:832-834).

[0013] Clinical Measurements of Memory Modulation Induced by Arousal

[0014] Arousal has also been demonstrated to affect memory performancein humans. Nielson et al. ((1996) Neurobiology of Learning and Memory66:133-142) studied the effects of muscle-tension-induced arousal onmemory storage and later retention performance. In that study, amoderate level of muscle-tension-induced arousal was produced by havingsubjects, young college students, squeeze a hand dynamometer at varioustimes during or following presentation of one practice and four 20-itemword lists presented as slides (one every 5 sec.). Thus, each subjectparticipated in four arousal conditions: no muscle tension; muscletension (100 sec.) during learning of the list (encoding); muscletension during the 100-sec. memory consolidation interval (storage); andmuscle tension (100 sec.) during the immediate recall of the words(retrieval). List order remained the same for all subjects, but theorder of arousal conditions was counterbalanced. A final recognitiontest was given 5 min. after completion of all lists. The resultsdemonstrated that muscle-tension-induced arousal during the memoryconsolidation interval significantly enhanced final recognitionperformance.

[0015] In another phase of this investigation, subjects were given aseries of two practice and twelve 200-word paragraphs to read. Half ofthe test paragraphs contained highlighted words. Immediately followingcompletion of each paragraph, two questions (one factual and onelogical-inferential) were asked about the content of that paragraph. Inaddition, for the paragraphs containing highlighted words, subjects wereasked to recall as many of the highlighted words as they could. For themuscle-tension arousal paragraphs, immediately after the paragraph wascompleted, the subject was handed the hand dynamometer and asked tosqueeze it during the answering of the questions and the recalling ofhighlighted words. Following completion of the final paragraph and allquestions, a final recognition test of all highlighted words was given.The results indicated significant enhancement of retention performancefor the muscle-tension arousal paragraphs compared to the no-tensionparagraphs, indicating that arousal can enhance memory storage in aworking-memory task.

[0016] This experiment was replicated using elderly subjects (Nielson etal. (1994) Behavioral and Neural Biology 62:190-200). In thisexperiment, there were 22 normotensive elderly subjects, 21 elderlysubjects taking either calcium-channel blockers orangiotensin-converting enzyme inhibitors to control hypertension, and 21elderly subjects taking beta-blocker antihypertensive medications. Thenormotensive elderly subjects and those taking non-beta-blockermedications all showed enhanced long-term memory performance as a resultof muscle-tension-induced arousal. However, those subjects chronicallytaking beta-receptor-antagonist medications showed no enhancement ofretention performance. These findings suggest that when arousal occurs,there is an enhanced release of adrenal catecholamines (epinephrine andnorepinephrine), and that these substances activate peripheral receptorsthat send neural messages to the brain to modulate memory storageprocesses. When these receptors are antagonized by beta-blocker-typeantihypertensive medications, the normal processes of memory modulationare impaired. Since epinephrine and norepinephrine do not freely crossthe blood-brain barrier, their release by arousal likely modulatesmemory by causing the transmission of neural messages to the brain,possibly via the vagus nerve pathway. Therefore, antagonizing peripheralbeta receptors by beta-blocker-type antihypertensive medicationsprevented the initiation of these messages by the receptors, thuseffectively attenuating the normally occurring modulation of memorystorage processes by arousal.

[0017] Possible Role of Specific Central Serotonergic and NoradrenergicPathways in the Modulation of Memory by Vagus Nerve Stimulation

[0018] The dorsal raphe nucleus is one of two monoaminergic brainstemnuclei, the other being the locus coeruleus, that receives indirectinput from vagal afferents. Both nuclei then project that information tovarious other brain structures implicated in learning and memoryprocesses, such as the amygdaloid complex, hippocampus, andmesencephalic reticular formation (Vertes et al. (1994) Journal ofComparative Neurology 340:11-26). Thus, the dorsal raphe nucleus andlocus coeruleus are well suited to regulate the memory-modulatingeffects of autonomic arousal. In addition, the dorsal raphe nucleusinteracts with the amygdaloid complex to produce conditioned fearresponses to inescapable shock and in learned-helplessness paradigms(Maier et al. (1993) Behavioral Neuroscience 107:377-788). Elevations inthe release of serotonin by the dorsal raphe nucleus also reportedlyincrease anxiety (Iversen (1984) Neuropharmacology 23:1553-1560). It istherefore possible that changes in autonomic activity and arousal arereflected in alterations of dorsal raphe nucleus activity and thesubsequent release of serotonin onto neurons found in the amygdaloidcomplex. It is therefore possible that changes in autonomic activity andarousal are transmitted to the brain via the vagus nerve and arereflected in alterations in the activity of neurons in the dorsal raphenucleus and the subsequent release of serotonin onto neurons of theamygdaloid complex, a brain structure well-known to be involved in themodulation of learning and memory.

[0019] Noradrenergic systems are also known to modulate memoryconsolidation and amygdaloid complex activity (cf. McGaugh (1989) AnnualReview of Neuroscience 12:255-287); however, Holdefer et al. ((1987)Brain Research 417:108-117) demonstrated that locus coeruleus-maintaineddischarge does not correlate with the memory modulation produced byperipherally-injected 4-OH amphetamine, D-amphetamine, or epinephrine.Although the locus coeruleus receives indirect vagal input, it alsoreceives serotonergic projections from the dorsal raphe nucleus.Consequently, dorsal raphe nucleus activity might suppress theresponsiveness of locus coeruleus neurons to autonomic stimulation,thereby increasing serotonergic control over the amygdaloid complex andother brain areas during the memory consolidation period. Thishypothesis is supported directly by studies of Naritoku et al.((1995) InAshley et al., Eds., Traumatic Brain Injury Rehabilitation, CRC Press,Boca Raton, pp. 43-65), which demonstrated activation of the locusceruleus and A5 nuclei, which are noradrenergic neurons. Preliminaryevidence of Krahl et al. ((1994) Society for Neuroscience Abstracts20:1453) also indicates that cells found in the dorsal locus coeruleusrespond differentially to those found in either the ventral locuscoeruleus or subcoeruleus following vagus nerve stimulation.

[0020] Modulation of Memory by Peripherally-acting Substances

[0021] Previous research has suggested that the vagus nerve plays a rolein the modulation of learning and memory brought about byperipherally-acting substances such as catecholamines, peptides, etc.(Williams et al. (1991) In Frederickson et al., Eds., Neuronal Controlof Bodily Function, Basic and Clinical Aspects: Volume 6, PeripheralSignaling of the Brain: Role in Neural-Immune Interactions, Learning andMemory, Hogrefe & Huber, Toronto, pp. 467-472; Williams et al. (1993)Physiology and Behavior 54:659-663; Flood et al. (1987) Science234:832-834). This work suggests that the vagus nerve may represent aneural pathway through which such substances alter retentionperformance. However, the effects of direct electrical activation of thevagus nerve on learning and memory in humans have not been previouslystudied.

[0022] Chemical vs. Direct Electrical Stimulation of the Vagus Nerve

[0023] 1. Chemical Stimulation

[0024] Hormonal or chemical (drug) agents function by interacting withspecific receptor proteins on neurons. When activated by aneurotransmitter, hormone, or drug, these receptor proteins theneither: 1) cause a chemical change in the cell, which indirectly causesion channels embedded in the membrane to either open or close, thuscausing a change in the electrical potential of the cell, or 2) directlycause the opening of ion channels, which causes a change in theelectrical potential of the cell. This change in electrical potentialthen triggers electrical events that are conducted to the brain by theaxons of sensory nerves such as those contained in the vagus.

[0025] Neural activity is constantly being controlled by the endogenousrelease of hormones, neurotransmitters, and neuromodulators. However,for therapeutic or experimental purposes, changes in neural activity canalso be produced by the administration of chemical or hormonal agents(drugs). When administered exogenously, these agents interact withspecific proteins either inside neurons or on the surface of the cellmembrane to alter cell function. Chemical agents can stimulate therelease of a neurotransmitter or family of neurotransmitters, block therelease of neurotransmitters, block enzymatic breakdown ofneurotransmitters, block reuptake of neurotransmitters, or produce anyof a wide variety of other effects that alter nervous systemfunctioning. A chemical agent can act directly to alter central nervoussystem functioning or it can act indirectly so that the effects of thedrug are carried by neural messages to the brain. A number ofchemical/hormonal agents such as epinephrine, amphetamine, ACTH,vasopressin, pentylene tetrazol, and hormone analogs all have been shownto modulate memory. Some act by directly stimulating brain structures.Others stimulate specific peripheral receptors.

[0026] 2. Electrical Stimulation

[0027] In contrast, electrical stimulation of a nerve involves thedirect depolarization of axons. When electrical current passes throughan electrode placed in close proximity to a nerve, the axons aredepolarized, and electrical signals travel along the nerve fibers. Theintensity of stimulation will determine what portion of the axons areactivated. A low-intensity stimulation will activate those axons thatare most sensitive, i.e., those having the lowest threshold for thegeneration of action potentials. A more intense stimulus will activate agreater percentage of the axons.

[0028] Electrical stimulation of neural tissue involves the placement ofelectrodes inside or near nerve pathways or central nervous systemstructures. Functional nerve stimulation is a term often used todescribe the application of electrical stimulation to nerve pathways inthe peripheral nervous system. The term neural prostheses describesapplications of nerve stimulation in which the electrical stimulation isused to replace or augment neural functions which have been damaged insome way. One of the earliest and most successful applications ofelectrical stimulation was the development of the cardiac pacemaker.More recent applications include the electrical stimulation of theauditory nerve to produce synthetic hearing in deaf patients, and theenhancement of breathing in patients with high-level spinal cord injuryby stimulation of the phrenic nerve to produce contractions of diaphragmmuscles. Recently, electrical stimulation of the vagus nerve is beingused to attenuate epileptic seizures.

[0029] The basis of the effects of electrical stimulation of neuraltissue comes from the observation that action potentials can bepropagated by applying a rapidly changing electric field near excitabletissue such as nerve or muscle tissue. In this case, the electricalstimulation, when passed through an electrode placed in close proximityto a nerve, artificially depolarizes the cell membrane which containsion channels capable of producing action potentials. Normally, suchaction potentials are initiated by the depolarization of a postsynapticmembrane. However, in the case of electrical stimulation, the actionpotentials are propagated from the point of stimulation along the axonto the intended target cells (orthodromic conduction). However, actionpotentials also travel from the point of nerve stimulation in theopposite direction as well (antidromic conduction).

[0030] Gold and his co-workers have demonstrated that administration ofglucose to rats or humans following a learning experience enhances laterretention performance (Gold, P. E. (1986) Behavioral and Neural Biology45:342-349; Manning et al. (1993) Neurobiology of Aging 14:523-528).Gold has suggested that vagus nerve stimulation may activate descendingefferent vagus pathways which directly and indirectly stimulate theliver to release glucose into the systemic circulation. This increasedplasma glucose has been postulated to serve as a second messenger tomodulate the storage of memories. However, the present investigatorsrecently demonstrated in rats that blocking descending vagus nervepathways by a topical application of the local anesthetic lidocaine tothe nerve did not attenuate memory enhancement produced by vagus nervestimulation (Clark, K. B., Smith, D. C., Hassert, D. L., Browning, R.B., Naritoku, D. K., and Jensen, R. A. (submitted for publication)).Posttraining electrical stimulation of vagal afferents with concomitantefferent inactivation enhances memory storage processes in the rat(Society for Neuroscience Abstracts, 22). These results clearly indicatethat the ascending neural messages resulting from vagus nervestimulation are the active agent mediating the observed enhancement inmemory storage processes.

[0031] Few experiments in contemporary neuroscience research employdirect nerve tract stimulation to alter global aspects of behavior suchas the storage of memories. Most researchers attempt to alter memoryand/or behavior by either administering a drug that activates specificneural systems or by electrically stimulating specific groups of neuronsin the central nervous system. Thus, the present inventors' discovery ofvagus nerve stimulated enhancement of particular neural processes asdisclosed herein is novel. In this case, stimulation of the vagus nerveresults in the activation of a variety of processes in the brain thatresult in changes in brain function. It is likely that only some ofthese processes are related to the modulation of memory storage and thatthis stimulation also modulates other changes or plastic processes inthe brain as well. That direct vagus nerve stimulation influencesplastic processes related to brain development or the recovery offunction from brain injury is a very good possibility given the alreadydemonstrated effect on one major form of neural plasticity, i.e., memorystorage.

[0032] Modulation of Memory in Rats by Electrical Stimulation of theVagus Nerve

[0033] Jensen and co-workers (Clark, K. B., Krahl, S. E., Smith, D. C.,and Jensen, R. A. (1994) Society for Neuroscience Abstracts 20: 802;Clark, K. B., Krahl, S. E., Smith, D. C., and Jensen, R. A. Neurobiologyof Learning and Memory 63:213-216) demonstrated that direct electricalstimulation of the vagus nerve at a particular intensity (0.4 mA) andfrequency (20 Hz) administered shortly after a learning experienceresulted in a pattern of effects on retention performance similar tothat reported following the administration of some drugs that do notfreely cross the blood-brain barrier (chemical stimulation of peripheralreceptors). In this experiment, vagus nerve stimulation (0.4 mA) givenduring the memory consolidation interval modulated later retentionperformance such that stimulated rats showed better memory. Stimulationat either a lower (0.2 mA) or higher (0.8 mA) intensity had no effect onretention.

[0034] Whether one could reasonably predict that this effect observed inrats might extrapolate to human beings is doubtful in view of thesubstantial differences in neuroanatomy and complexity of memoryprocesses between laboratory rodents and humans. The experimentsperformed in rats were based on a single-trial training task of greatsimplicity, i.e., an inhibitory avoidance task. In this task, theanimals were placed in a runway, one end of which was brightlyilluminated, while the other end was darkened. As rats are nocturnal,burrowing animals, they typically move quickly from the lighted end intothe darkened end when the door separating the two ends of the runway isopened. A mild electrical footshock was delivered in the darkened end.Immediately thereafter, each animal was removed from the runway andreturned to its home cage, where it received either no stimulation orvagal stimulation through chronically implanted cuff electrodes on theleft cervical vagus nerve. Retention was tested 24 hours later. Latencyto step through into the darkened end was taken as the measure ofretention.

[0035] In the case of human memory, especially verbal memory, the neuralsystems involved are much more complex than those involved in thelearning of a simple avoidance training task by the rat. Learning ofconcepts, vocabulary, and procedures by humans is qualitatively andquantitatively different from a rat's learning to avoid the end of arunway where punishment, i.e., a footshock, has occurred. Many humanbrain structures, such as those that mediate language, for example, donot even exist in the laboratory rat. It is therefore possible that theforegoing phenomenon observed in rats is limited to infrahumans, and itis therefore not reasonably predictable that vagal nerve stimulationmodulation of memory in the laboratory rat would generalize to humansubjects. The applicability of vagal nerve-stimulated modulation oflearning of tasks such as complex verbal tasks has for the first timebeen demonstrated by the present inventors as disclosed herein.

[0036] Uniqueness of Vagus Nerve Stimulation in Modulating Memory

[0037] Vagus nerve stimulation is completely unlike other experimentalmanipulations known to modulate memory. Drugs, hormones, and electricalbrain stimulation are all known to alter memory storage processes. Forexample, administration of adrenal hormones (such as epinephrine) orpituitary hormones (such as ACTH) after a learning experience results inthe enhancement of memory in a dose-dependent manner. Very low doses arewithout effect; intermediate doses tend to improve retentionperformance; very high doses tend to cause amnesia. These hormonalsubstances and pharmacological agents are thought to act on memoryprocesses by activating specific receptors in the periphery which, inturn, send neural messages to the brain to either enhance or impair thestorage of memories.

[0038] In contrast, vagus nerve stimulation directly activates oneprincipal nerve pathway connecting the central nervous system withperipheral structures located in the viscera. In this case, the step ofchemically activating receptors in the periphery is avoided. Rather,action potential messages in the nerve are directly triggered by theelectrical stimulation. These messages pass along the vagus nerve andactivate those brain structures in which the nerve fibers terminate. Theresult is release of neurotransmitters and activation of still otherbrain structures. Following this, there are alterations in brainfunction such as the well-established reduction in epileptic seizuresand the recently demonstrated enhancement in CNS plasticity,specifically, facilitation of memory storage processes.

[0039] Brain Neural Plasticity

[0040] The term “neural plasticity” can be viewed as encompassing thosestructural alterations in the brain that lead to changes in neuralfunction. Such changes in neural function then lead to changes inbehavior or in the capacity for behavior. Learning and memory can bethought of as one common form of neural plasticity. The storage ofmemories following a learning experience is the result of structural andfunctional changes that occur in specific groups of neurons. Every timesomething is learned, there is a change in that organism's nervoussystem which encodes that new information. Such a change does notnecessarily result in an immediate change in behavior; rather, itresults in an alteration in behavior potential.

[0041] During development of the nervous system both before and afterbirth, there are profound plastic changes taking place which shape thestructure and function of the brain. Before birth, groups of nerve cellsform, migrate to their assigned location in the brain, and then makeconnections with other cells. Following birth, neurons continue tosprout new projections, and these branches expand dramatically incomplexity, sometimes extending great distances, and making connectionswith other cells of the nervous system. This process, another form ofneural plasticity, continues at a decreasing rate from the time of birthuntil adolescence.

[0042] Neural plasticity is thought to be moderated by a wide variety ofcellular and molecular events, including transcription and translationof DNA, which produces cellular proteins that cause long-term changes inneuronal function. One such signal is thought to be the protein fos,which is produced by neurons under conditions of high activity. Thisprotein signals the transcription of other proteins, and is thought tomediate long-term neuronal changes. It may be induced by severalneurotransmitters, including excitatory amino acids and monoamines.Naritoku et al. ((1995) Epilepsy Research 22:53-62) demonstrated thatfos is induced by stimulation of the vagus nerve in widespread areas ofthe brain (see FIG. 3), thus demonstrating that vagus nerve stimulationactivates many areas in the brain, and furthermore, appears to inducethe production of a protein that causes further transcriptional eventsthat may in turn mediate neural plasticity.

[0043] Memory and Learning, and their Modulation

[0044] It is clear that learning and memory are not unitary processesand that there are different types of memory that are mediated bydifferent brain structures. On one level of analysis, it is possible todistinguish between two broad classes of memories, “explicit” and“implicit.” When explicit memory is to be assessed, measures such asrecall and recognition are used. These measures depend on the consciousrecollection of previously stored information. Recognition performanceis generally considered to be among the most sensitive measures ofexplicit memory. Tests of implicit memory infer learning from theeffects that experience or practice has on the subject's performance.For example, prior exposure to words will enhance later performance inrecognizing these words when they are flashed very rapidly on a screenor presented as word fragments.

[0045] Another distinction between types of memory is that between“procedural” and “declarative” memories. These are typically defined as“knowing how” and “knowing that.” Procedural memories includeperceptual, cognitive, and motor skills, while declarative memoryincludes such things as facts, events, and routes between places. Bothforms of memory can be modulated by various agents, although declarativememories are more subject to disease-produced amnesia than areprocedural memories.

[0046] We know from our own every-day experiences that some occurrencesor events are remembered clearly while others are remembered poorly orperhaps not at all. This is true of procedural and declarative memorieswhether assessed implicitly or explicitly. It is well established inlaboratory animals that retention can be either impaired or enhanced byexperimental treatments such as electrical brain stimulation, theadministration of stimulant drugs, or the administration of hormones(McGaugh et al. (1972) Memory Consolidation, San Francisco, AlbionPublishing Company). What is commonly reported is that retentionperformance, measured some time after the learning experience, can bemodulated by changing the parameters of training or by theadministration of chemical stimulation shortly after the time oftraining. Although the underlying mechanisms that mediate memorymodulation are not well understood, it appears that several commonprinciples may mediate differences in the quality of remembering.

[0047] One major variable influencing retention performance appears tobe level of arousal. Early in the development of the behavioralsciences, the Yerkes-Dodson principle was described (Yerkes et al.(1908) Journal of Comparative Neurology and Psychology 18:459-482). Thisprinciple is characterized by an inverted U-shaped relationship betweenthe amount of motivation or arousal and the resultant level ofbehavioral performance. This relationship can be seen between the levelof arousal and the effectiveness of memory storage processes. Forexample, either low or very high levels of arousal produce relativelypoor learning and memory. However, an intermediate level of arousalresults in relatively good memory for a learning experience (McGaugh, J.L. (1973) Annual Review of Pharmacology 13:229-241). A similar curveshowing an inverted U-shaped function is seen in the data obtained usinglaboratory rats and vagus nerve stimulation delivered after training. Itis important to note that memory is modulated by post-trainingtreatment. In such an experiment, the learning occurs in a normal stateand then after training, the treatment is administered. Thus, theprimary effects of the treatment are on the storage of the memory andnot on other aspects of the experience such as perception or level ofmotivation.

[0048] Traumatic Brain Injury

[0049] Another form of neural plasticity is recovery of functionfollowing brain injury. As in the case of memory formation or braindevelopment, in this case too there is a change in the ways that neuronsinteract with one another. When neurons are lost due to disease ortrauma, they are not replaced. Rather, the remaining neurons must adaptto whatever loss occurred by altering their function or functionalrelationship relative to other neurons. Following injury, neural tissuebegins to produce trophic repair factors, such as nerve growth factorand neuron cell adhesion molecules, which retard further degenerationand promote synaptic maintenance and the development of new synapticconnections. However, as the lost cells are not replaced, existing cellsmust take over some of the functions of the missing cells, i.e., theymust “learn” to do something new. In part, recovery of function frombrain traumatic damage involves plastic changes that occur in brainstructures other than those damaged. Indeed, in many cases, recoveryfrom brain damage represents the taking over by healthy brain regions ofthe functions of the damaged area. Thus, such recovery can be viewed asthe learning of new functions by uninjured brain areas to compensate forthe loss of function by other regions. Studies of the effect of vagusnerve stimulation onfos production demonstrate that such stimulationinduces transcriptional events that produce proteins which in turnstimulate further cellular transcriptional activity (Hughes et al.(1995) Pharmacol. Rev. 47:133-178). Increases in neuronal cellularactivity will enhance the recovery of function after traumatic braininjury.

[0050] Traumatic brain injury results from a wide variety of causesincluding, for example, blows to the head from objects; penetratinginjuries from missiles, bullets, and shrapnel; falls; skull fractureswith resulting penetration by bone pieces; and sudden acceleration ordeceleration injuries.

[0051] Traumatic brain injury represents a growing medical problem inthe United States and elsewhere. It is an extremely costly illness, notonly due to the expenses arising from the acute care required, but alsodue to the costs associated with rehabilitation and any resultinglong-term disability. A therapy that would accelerate the recoveryprocess and/or improve outcome would be highly beneficial to afflictedpersons. As many as 40% of persons with severe head injury proceed todevelop epilepsy, which further impedes functional recovery fromtraumatic brain injury. In addition, epilepsy itself further limitsfunction in this population. A therapy that prevents the genesis ofepilepsy would therefore significantly benefit traumatically braininjured persons.

[0052] Memory Disorders

[0053] A third form of neural plasticity relates to the treatment ofchronic memory disorders. These disorders arise from, for example,Alzheimer's Disease, encephalitis, cerebral palsy, Wemicke-Korsakoff(alcohol-related) syndrome, brain injury, post-temporal lobectomy,Binswanger disease, Parkinson's disease, Pick's disease, stroke,multi-stroke dementia, multiple sclerosis, post arrest hypoxic injury,near drowning, etc.

SUMMARY OF THE INVENTION

[0054] As demonstrated in the non-limiting Examples disclosed infra,vagus nerve stimulation employed with the appropriate parameters canimprove memory and learning in human and animal subjects. When deliveredshortly after a learning experience, vagus nerve stimulation results inthe initiation of nerve impulses that travel to those brain structureswhere the nerve terminates, predominantly the nucleus of the solitarytract. The resultant release of neurotransmitters and activation ofcells in the vagus nerve target structures results in the activation ofother brain areas including those such as the amygdala and hippocampusthat are known to be involved in memory storage and the modulation ofmemory. The result is facilitated memory storage (consolidation) andimproved retention performance when memory is measured at some latertime. Vagus nerve stimulation can also be employed in the treatment ofhuman and animal subjects suffering from various forms of brain damageor from traumatic head injury.

[0055] It is well known that central nervous system neurons do notregenerate following loss due to disease or injury. Therefore, in orderfor there to be recovery of function, healthy areas of the brain must“learn” to take over the functions of the damaged area.

[0056] As discussed above, both phenomena are manifestations of brainneural plasticity.

[0057] Briefly, therefore, the present invention provides a number ofmethods of influencing various aspects of brain neural plasticity. Inone embodiment, the present invention is directed to a method ofmodulating brain neural plasticity in a human or animal subject. Themethod comprises applying a stimulating electrical signal to the vagusnerve of a human or animal subject. The stimulating electrical signalbeing effective to cause a physiological, structural, or neuronalconnective alteration in the brain. Neural function in the brain ischanged as a consequence of the neuronal connective alteration; therebychanging behavior, or the capacity for behavior, in the human or animalsubject.

[0058] In another embodiment, the present invention is directed to amethod of improving learning or memory in a human or animal subject. Themethod comprises

[0059] (a) applying a stimulating electrical signal to the vagus nerveof a human or animal subject, the stimulating electrical signal beingeffective to enhance memory storage or consolidation processes in thehuman or animal subject; and (b) improving memory storage or improvingthe retention of learning experiences, in the human or animal subject.

[0060] In another embodiment, the present invention is directed to amethod of treating a human or animal subject suffering from a symptomcaused by traumatic brain injury or characteristic of traumatic braininjury. The method comprises selecting a human or animal subjectsuffering from a symptom caused by traumatic brain injury orcharacteristic of traumatic brain injury; and applying a stimulatingelectrical signal to the vagus nerve of the human or animal subject, thestimulating electrical signal being effective to alleviate the symptomcaused by or characteristic of traumatic brain injury. The methodfurther comprises monitoring the human or animal subject via a memberselected from the group consisting of clinical outcome, a clinical test,a laboratory test, and combinations thereof, to determine if the symptomhas been alleviated, or if further stimulation of the vagus nerve isrequired. If required, the vagus nerve is further stimulated and thesubject is further monitored as in the preceding steps, until thesymptom has been alleviated.

[0061] In another embodiment, the present invention is directed to amethod of preventing the development of epilepsy in a human or animalsubject. The method comprises selecting a human or animal subjectpredisposed to, or rendered susceptible to, developing epilepsy; andapplying a stimulating electrical signal being effective to preventepilepsy to the vagus nerve of the human or animal subject. The methodfurther comprises monitoring the subject to determine if furtherstimulation of the vagus nerve is required to prevent epilepsy in thesubject; and if required, further stimulating the vagus nerve andmonitoring the subject as in the preceding steps, to prevent developmentof epilepsy in the subject.

[0062] In another embodiment, the present invention is directed to amethod of treating a human or animal subject suffering from a symptomselected from the group consisting of memory impairment, a learningdisorder, impairment of cognitive processing speed, impairment ofacquisition of perceptual skills, impairment of acquisition of motorskills, and impairment of perceptual processing. The method comprisesselecting a human or animal subject suffering from a symptom selectedfrom the group consisting of memory impairment, a learning disorder,impairment of cognitive processing speed, impairment of acquisition ofperceptual skills, impairment of acquisition of motor skills, andimpairment of perceptual processing; and applying a stimulatingelectrical signal to the vagus nerve of the human or animal subject. Theelectrical signal is characterized as being effective to alleviate thesymptom in the human or animal subject. The method further comprisesmonitoring the human or animal subject via a method selected from thegroup consisting of a clinical test, a laboratory test, determination ofclinical outcome, and combinations thereof, to determine if the symptomhas been alleviated, or if further stimulation of the vagus nerve isrequired to alleviate the symptom; and if required, further stimulatingthe vagus nerve and monitoring the human or animal subject as in thepreceding steps, until the symptom has been alleviated.

[0063] In another embodiment, the present invention is directed to amethod of treating a human or animal subject suffering from persistentimpairment of consciousness. The method comprises selecting a human oranimal subject suffering from persistent impairment of consciousness;and applying a stimulating electrical signal to the vagus nerve of thehuman or animal subject. The stimulating electrical signal ischaracterized as being effective to alleviate the persistent impairmentof consciousness in the human or animal subject. The method furthercomprises monitoring the human or animal subject via determination ofclinical outcome to determine if the persistent impairment ofconsciousness has been alleviated, or if further stimulation of thevagus nerve is required to alleviate the persistent impairment ofconsciousness; and if required, further stimulating the vagus nerve andmonitoring the human or animal subject as in the preceding steps, untilthe persistent impairment of consciousness has been alleviated.

[0064] Further scope of the applicability of the present invention willbecome apparent from the detailed description and drawings providedbelow. However, it should be understood that the detailed descriptionand specific examples, while indicating preferred embodiments of thepresent invention, are given by way of illustration only since variouschanges and modifications within the spirit and scope of the inventionwill become apparent to those skilled in the art from this detaileddescription.

BRIEF DESCRIPTION OF THE DRAWINGS

[0065] The foregoing and other objects, features, and advantages of thepresent invention will be better understood from the following detaileddescription taken in conjunction with the accompanying drawings, all ofwhich are given by way of illustration only and which are not limitativeof the present invention, in which:

[0066]FIG. 1 is a bar graph showing the effect of vagus nervestimulation given shortly after a learning experience, collapsed acrossGamma and Delta Group patients. Eleven subjects silently read paragraphscontaining highlighted words. Word recognition performance was enhancedby vagus nerve stimulation delivered during the memory consolidationinterval. Stimulation intensity was 0.5 mA, biphasic pulses, 30 Hz.Highlighted words that were paired with vagus nerve stimulation wererecognized with greater frequency (t(9)=2.78,p<0.03) than baselinecontrol words (not paired with stimulation).

[0067]FIG. 2 is a bar graph showing the effect of vagus nervestimulation at tolerance intensities for the Gamma Group. Subjects weretested 2 weeks, 4 weeks and 16 weeks after implantation of theneurocybemetic prosthesis. Recognition performance of highlighted wordsfollowing stimulation was compared to baseline (no stimulation). Vagusnerve stiumlation delivered during the memory consolidation intervalsignificantly enhanced retention performance only at Test 1 given 2weeks after implantation with a 0.5 mA intensity. Stimulation was rampedup to tolerance level after Test 2 and stimulation intensity averaged1.2 mA on Tests 2 and 3. It is unclear whether the decrement in themagnitude of the effect is due to the increased stimulation intensity orto a reduction in effect with the passage of time.

[0068]FIG. 3 is a camera lucida drawing of fos immunolabeling in thebrain induced by vagus nerve stimulation for three hours (from FIG. 4 ofNaritoku et al. (1995) Epilepsy Research 22:53-62). The sections aredisplayed from caudal to rostal levels (left to right), with therelative abundance of labeled nuclei represented by the density of thedots in the drawings. Note the immunolabeling in the cingulate, andretrosplenial cortex, and in the amygdala. In the thalamus, there islabeling in the habenula, lateral posterior nucleus, and marginal zoneof the medial geniculate body, and in the hypothalamus there is labelingin the ventromedial and arcuate nuclei. In the brainstem there isimmunolabeling in the locus ceruleus, A5 nuclei and cochlear nuclei(Abbreviations: A5=A5 nucleus; Arc=arcuate nucleus; Cg=cingulate cortex;HbN=Habenular nucleus; LC=locus ceruleus; LPMC=Lateral postr thalamicnucleus; MZMG=marginal zone of medial geniculate; PMCO=postr medialcortical amygdalar nucleus; PVP=paraventricular nucleus of thalamus;RS=retrosplenial cortex; RSG=retrosplenial granular cortex; VC=ventralcochlear nucleus; VMH=ventromedial hypothalamic nucleus).

[0069]FIG. 4 is a graph showing the antiepileptogenic effect of vagusnerve stimulation in the rat electrical kindling experiment described inExample 5.

DETAILED DESCRIPTION OF THE INVENTION

[0070] The following detailed description of the present invention isprovided to aid those skilled in the art in practicing the same. Evenso, the following detailed description should not be construed to undulylimit the present invention as modifications and variations in theembodiments discussed herein may be made by those of ordinary skill inthe art without departing from the spirit or scope of the presentinventive discovery.

[0071] The contents of each of the references cited in the presentspecification are herein incorporated by reference in their entirety.

[0072] Devices for Electrical Stimulation of the Vagus Nerve

[0073] The methods of the present invention rely upon modulatedelectrical stimulation of the vagus nerve. Such electrical stimulationcan be achieved by a variety of different methods known in the art. Byway of example, such electrical stimulation can be achieved via the useof a neurostimulating device which can be, but does not necessarily haveto be, implanted within the subject's body. Forms of neurostimulatingdevices or accessories therefor that can be employed in the methodsdisclosed herein are described in U.S. Pat. Nos. 4,573,481; 4,702,254;4,867,164; 4,920,979; 4,979,511; 5,025,807; 5,154,172; 5,179,950;5,186,170; 5,215,089; 5,222,494; 5,235,980, 5,237,991; 5,251,634;5,269,303; 5,304,206; and 5,351,394.

[0074] While the reader is referred to the disclosures of thesedocuments for details of various neurostimulating devices useful in thepresent methods, certain aspects thereof can be summarized as followsfor the reader's convenience.

[0075] The neurostimulator can utilize a conventional microprocessor andother standard electrical and electronic components, and in the case ofan implanted device, communicates with a programmer and/or monitorlocated externally to the subject's body by asynchronous serialcommunication for controlling or indicating states of the device.Passwords, handshakes, and parity checks can be employed for dataintegrity. The neurostimulator also includes means for conservingenergy, which is important in any battery operated device, andespecially where the device is implanted for medical treatment, andmeans for providing various safety functions, such as preventingaccidental reset of the device.

[0076] The stimulus generator can be implanted in the patient's body ina pocket formed by the surgeon just below the skin in the chest in muchthe same manner as a cardiac pacemaker would be implanted, although aprimarily external neurostimulator can also be employed. Theneurostimulator also includes implantable stimulating electrodes,together with a lead system for applying the output signal of thestimulus generator to the patient's vagus nerve. Components external tothe patient's body include a programming wand for telemetry of parameterchanges to the stimulus generator and monitoring signals from thegenerator, and a computer and associated software for adjustment ofparameters and control of communication between the generator, theprogramming wand, and the computer.

[0077] In conjunction with its microprocessor-based logic and controlcircuitry, the stimulus generator can include a battery or set ofbatteries which can be of any reliable, long-lasting type conventionallyemployed for powering implantable medical electronic devices, such asthose employed in implantable cardiac pacemakers or defibrillators. In apreferred embodiment of the stimulus generator, the battery can be asingle lithium thionyl chloride cell. The terminals of the cell areconnected to the input side of a voltage regulator which smoothes thebattery output to produce a clean, steady output voltage, and providesenhancement thereof such as voltage multiplication or division ifrequired.

[0078] The voltage regulator supplies power to the logic and controlsection, which includes a microprocessor and controls the programmablefunctions of the device. Among these programmable functions are outputcurrent, output signal frequency, output signal pulse width, outputsignal on-time, output signal off-time, daily treatment time forcontinuous or periodic modulation of vagal activity, and outputsignal-start delay time. Such programmability allows the output signalto be selectively crafted for application to the stimulating electrodeset to obtain the desired modulation of vagal activity. Timing signalsfor the logic and control functions of the generator are provided by acrystal oscillator.

[0079] A built-in antenna enables communication between the implantedstimulus generator and the external electronics, including bothprogramming and monitoring devices, to permit the device to receiveprogramming signals for parameter changes, and to transmit telemetryinformation from and to the programming wand. Once the system isprogrammed, it can operate continuously at the programmed settings untilthey are reprogrammed by means of the external computer and theprogramming wand.

[0080] The logic and control section of the stimulus generator controlsan output circuit or section which generates the programmed signallevels appropriate for the condition being treated. The output sectionand its programmed output signal are coupled (directly, capacitively, orinductively) to an electrical connector on the housing of the generatorand to a lead assembly connected to the stimulating electrodes. Thus,the programmed output signal of the stimulus generator can be applied tothe electrode set implanted on the subject's vagus nerve to modulatevagal activity in the desired manner.

[0081] The housing in which the stimulus generator is encased ishermetically sealed and composed of a myaterial such as titanium, whichis biologically compatible with the fluids and tissues of the subject'sbody.

[0082] The implanted stimulus generator can be placed in the subject'schest in a cavity formed by the implanting surgeon just below the skin,much as a pacemaker pulse generator would be implanted. A stimulatingnerve electrode set is conductively connected to the distal end of aninsulated electrically conductive lead assembly attached at its proximalend to a connector. The electrode set can be a bipolar stimulatingelectrode of the type described in U.S. Pat. No. 4,573,481. Theelectrode assembly is surgically implanted on the vagus nerve in thepatient's neck. The two electrodes are wrapped about the vagus nerve,and the assembly can be secured to the nerve by a spiral anchoringtether such as that disclosed in U.S. Pat. No. 4,979,511. The lead(s)is(are) secured, while retaining the ability to flex with movement ofthe chest and neck, by a suture connection to nearby tissue.

[0083] The stimulus generator can be programmed using a personalcomputer employing appropriate software and a programming wand. The wandand software permit non-invasive communication with the generator afterthe latter is implanted, which is useful for both activation andmonitoring functions. Programming capabilities should include theability to modify the adjustable parameters of the stimulus generatorand its output signal, to test device diagnostics, and to store andretrieve telemetered data.

[0084] Diagnostics testing should be implemented to verify properoperation of the device. The nerve electrodes are capable of indefiniteuse absent indication of a problem with them observed on such testing.

[0085] Although an implantable device for vagus nerve stimulation hasbeen described, it will be apparent to those skilled in the art from theforegoing description that variations and modifications thereof can bereadily made. For example, rather than employing a totally implantable**device, one can employ an electronic energization package that isprimarily external to the body. Stimulation can be achieved with an RFpower device implemented to provide the necessary energy level. Theimplanted components may be limited to the lead/electrode assembly, acoil, and a DC rectifier. Pulses programmed with the desired parameterswould be transmitted through the skin with an RF carrier, and the signalthereafter rectified to regenerate a pulsed signal for application asthe stimulus to the vagus nerve to modulate vagal activity. This wouldvirtually eliminate the need for battery changes.

[0086] An external stimulus generator can be employed, with leadsextending percutaneously to the implanted nerve electrode set.

EXAMPLE 1 Modulation of Brain Neural Plasticity by Vagus NerveStimulation

[0087] As noted above, the concept of neural plasticity encompassesstructural alterations in the brain that lead to changes in neuralfunction. Changes in neural function then lead to changes in behavior,or in the capacity or potential for behavior.

[0088] The present inventors have concluded that brain neural plasticityin humans and animals can be modulated by vagus nerve stimulation by thefollowing steps:

[0089] (a) applying to the vagus nerve of said human or animal astimulating electrical signal having parameters sufficient to cause aphysiological, structural, or neuronal connective alteration in thebrain;

[0090] (b) changing neural function in said brain as a consequence ofsaid alteration; and;

[0091] (c) changing behavior or the capacity for behavior in said humanor animal subject.

[0092] Specifically, brain neural plasticity can be modulated asfollows.

[0093] Apparatus

[0094] The neurostimulating device and electrodes can be implanted asdescribed in U.S. Pat. Nos. 5,154,172 and 5,269,303, although anyconventional devices known in the art can be employed.

[0095] Stimulation Parameters of the Output Signal

[0096] The preferred range of stimulation parameters of the outputsignal of the stimulus generator for modulation of brainneuroplasticity, and the typical value of each parameter of the outputsignal programmed into the device can be as follows.

[0097] The pulse width can be in the range of from about 50 μsec. toabout 1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec.,more preferably from about 250 μsec. to about 750 μsec., even morepreferably from about 400 μsec. to about 750 μsec., and most preferablyfrom about 400 μsec. to about 600 μsec. A pulse width of about 400 μsec.to about 750 μsec. is appropriate when C fiber activation is required ordesired. If only A and B fiber activation is required or desired, then apulse width of about 50 μsec. to about 250 μsec. would be effective. Thetype of fiber activation can vary between individual patients.

[0098] The output current can be in the range of from about 0.1 mA toabout 10 mA, more preferably from about 0.1 mA to about 6 mA, mostpreferably from about 0.1 mA to about 4 mA.

[0099] The frequency of the output signal can be in the range of fromabout 1 Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz,most preferably from about 10 Hz to about 40 Hz.

[0100] The pulses can be monophasic, biphasic, or a combination thereof.

[0101] The train duration of the output current can be in the range offrom about 1 sec. to 1,5 about 4 hours, more preferably from about 2.5sec. to about 2.5 hours, most preferably from about 5 sec. to about 1hour. The interval between trains can be in the range of from about 1sec. to about 1 week, more preferably from about 1 sec. to about 1 day,most preferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand.

[0102] As will be recognized by those of ordinary skill in the art, anyor all of the foregoing vagus nerve stimulation parameters can betitrated clinically to achieve the desired response in a patient.

EXAMPLE 2 Improvement of Memory and Learning by Vagus Nerve Stimulation

[0103] Methods and Design

[0104] Learning Experiences

[0105] The learning experiences to which the methods described hereincan be applied include those which are physical, mental, or acombination thereof. As discussed above, learning and memory, one formof neural plasticity, can take many forms. Most commonly, memories areclassified as being either procedural or declarative. Further, there area number of different aspects to each kind of memory. Procedurallearning and memory, characterized as knowing how to perform some act,can include the learning and remembering of motor skills, perceptualabilities, and cognitive capabilities. Declarative learning and memory,knowing specific kinds of factual information, can include the knowledgeof isolated and connected facts, the events and episodes of one'slifetime, and the routes and pathways of everyday life. As noted supra,each of these kinds of memory is the result of neural plasticity takingplace in the brain, and because each can be modulated by peripherallyadministered chemical agents which do not cross the blood-brain barrier,their mode of action is likely to be through the action of receptors inthe viscera that trigger nerve impulses which travel along the vagusnerve to targets in the brain. Hence, the storage of these forms ofmemory can be modulated by direct stimulation of the vagus nerve,bypassing the need to activate neural receptors in the viscera.

[0106] Apparatus

[0107] The device and electrodes can be implanted as described in U.S.Pat. Nos. 5,154,172 and 5,269,303, although any comparable device knownin the art can be employed.

[0108] Stimulation Parameters of the Output Signal

[0109] Vagus nerve stimulation subsequent to exposure of a human oranimal subject to a learning experience in order to improve learning ormemory in that subject can be performed by employing a range ofstimulation parameter values of the output signal of the stimulusgenerator.

[0110] The pulse width can be in the range of from about 50 μsec. toabout 1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec.,more preferably from about 250 μsec. to about 750 μsec., even morepreferably from about 400 μsec. to about 750 μsec., and most preferablyfrom about 400 μsec. to about 600 μsec. A pulse width of about 400 μsec.to about 750 μsec. is appropriate when C fiber activation is required ordesired. If only A and B fiber activation is required or desired, then apulse width of about 50 μsec. to about 250 μsec. would be effective. Thetype of fiber activation can vary between individual patients.

[0111] The output current employed for the signal should be of amoderate or intermediate intensity, and can be in the range of fromabout 0.1 mA to about 10 mA, more preferably from about 0.1 mA to about6 mA, most preferably from about 0.1 mA to about 4 mA.

[0112] The frequency of the output signal can be in the range of fromabout 1 Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz,most preferably from about 10 Hz to about 40 Hz.

[0113] The output signal can be monophasic, biphasic, or a combinationthereof.

[0114] The train duration of the output current can be in the range offrom about 1 sec. to about 4 hours, more preferably from about 2.5 sec.to about 2 hours, more preferably from about 5 sec. to about 1 hour, andmost preferably about 30 sec. The interval between trains can be in therange of from about 1 sec. to about 60 sec., more preferably from about2.5 sec. to about 45 sec., most preferably from about 5 sec. to about 30sec.

[0115] The time period after exposure of the human or animal subject toa learning experience in which electrical stimulation of the vagus nerveto improve memory or learning can occur can be in the range of fromabout 0.01 sec. to about 30 min., more preferably about 0.05 sec. toabout 20 min., most preferably about 0.1 sec. to about 15 min. Thememory consolidation period in humans typically lasts for 30 minutesafter the conclusion of acquisition.

[0116] As will be recognized by those of ordinary skill in the art, anyor all of the foregoing vagus nerve stimulation parameters can betitrated by routine experimentation to achieve the desired memoryenhancement response in a particular subject.

[0117] The improved storage of the memory or retention of the learningexperience can be observed hours, days, weeks, months, or years afterexposing or subjecting a human or animal subject to the learningexperience.

[0118] Stimuli and Tests for Human Testing

[0119] Fourteen narrative paragraphs were used as stimuli in thisexperiment. Each paragraph was approximately 200 words in length, ofappropriate reading level for each subject, and each was typed on aseparate page. When presented to the subjects, each paragraph wascovered with a cardboard mask that revealed only two lines of text at atime. Subjects were instructed to read at a comfortable pace and to movethe mask down the page as the paragraph was read. Subjects were toldthat they would be questioned about the paragraphs later, and that themask was being used to prevent reviewing of the material. Two versionsof each paragraph were prepared. In one version, seven words werehighlighted using a yellow marking pen, and subjects were told that amemory test for these words would follow questions about the paragraph.In the other set of paragraphs, no words were highlighted. Words chosenfor highlighting were common nouns, and were distributed equallythroughout each paragraph.

[0120] In each block of seven paragraphs, the first paragraph wasshorter and simpler than the subsequent paragraphs, and served as awarm-up paragraph. Data from these warm-up paragraphs were not includedin the analysis. For the six test paragraphs in each block, three“loaded” paragraphs (paragraphs with highlighted words to be remembered)were alternated with three “unloaded” paragraphs (no highlighted words).In addition, in one of the two blocks of paragraphs, stimulation of thevagus nerve occurred, while in the other block, the loaded trials werenot associated with vagus nerve stimulation. Whether vagus nervestimulation occurred in the first or second block of paragraphs wascounterbalanced across subjects. The overall design of this experimentis summarized in Table 1. TABLE 1 Summary of Experimental Design 1 2 3 45 6 7 Break 8 9 10 11 12 13 14 1 X A B C D E F X G H I J K L 2 X B A D CF E X H G J I L K 3 X A B C D E F X G H I J K L 4 X B A D C F E X H G JI L K

[0121] Letters A-L and X represent the paragraphs of text that were readby the subjects; rows represent the four condition orders. Underlinesindicate that highlighted word was present in the paragraphs; italicsindicate that stimulation of the vagus nerve was given following readingof the paragraph. Subjects were assigned to an experimental conditionvia Latin-square rotation.

[0122] Procedure for Human Testing

[0123] Each subject was given a brief summary of the procedure used inthis study at each visit (i.e., visits 2, 5, and 7), and any questionswere answered prior to testing. Visit 2 testing served as apre-implantation baseline consisting of paragraph reading followed byinferential, logical, and retention queries. The procedures for thisvisit were identical to those discussed below for visits 5 and 7, exceptthat vagus nerve stimulation was not administered. The first series (5stimulations) of vagus nerve stimulations were given to subjects duringvisit 5 at an intensity of 0.5 mA with a frequency of 30 Hz (Gamma) orminimal perceptible current (0.25-1 mA) at 1 Hz (Delta). During thistime, the reaction of the subject was studied, and appropriateadjustments were made. This enabled each subject to become acquaintedwith the sensations produced by the stimulation, and helped to minimizepossible effects of novelty produced by the sensations associated withstimulation. It is important to eliminate any novelty effects producedby the stimulation.

[0124] At that time, during Visit 5, those subjects in the Gamma Groupreceived vagus nerve stimulation at 0.5 mA, 30 Hz. Those in the DeltaGroup received threshold stimulation to perception (0.25 to 1.0 mA) onceevery 180 minutes. Following stimulation, a one-hour rest period wasgiven to ensure that any residual effects resulting from these firstexposures to the stimulation current were minimized before memorytesting procedures began. Ramping procedures began following completionof the memory testing procedure on Visit 5.

[0125] Following the one-hour rest period, subjects were asked to read apractice paragraph (paragraph X in Table 1) to familiarize them with theuse of the cardboard mask during reading. A two-minute rest periodfollowed to allow dissipation of any arousal that might have occurred.Pulse rate and blood pressure were measured at the end of this restperiod. The two blocks of six paragraphs each were then administered.There was a five-minute rest period following administration of thefirst block of paragraphs and the beginning of the second. A warm-upparagraph was also given at the start of the second block of paragraphs.Immediately following completion of each paragraph, pulse rate and bloodpressure were recorded and two questions, one factual and onelogical-inferential, were asked about the content of that paragraph. Inaddition, for the loaded paragraphs, subjects were asked to recall thehighlighted words following answering of the two questions. For thoseparagraphs to be paired with vagus-nerve stimulation, immediately aftereach subject in the Gamma Group completed reading the paragraph andanswering the questions, she/he was given vagus nerve stimulation for 30sec. Those subjects in the Delta Group received no stimulation.

[0126] Following completion of the final paragraph and the answering ofquestions, an unannounced recognition test of all highlighted words wasgiven. In this test, a list of all 42 highlighted target words wasrandomly interspersed with 210 distractor words (16.6% target words).The distractor words were highly concrete imageable nouns (Pavio et al.(1968). Concreteness, imagery, and meaningfulness values for 925 nouns.Journal of Experimental Psychology, 76, (Suppl), 1-25). Subjects wereasked to mark all words which they believed had been previouslypresented as highlighted words in the paragraphs they had read earlier.When this test was completed, pulse rate and blood pressure weremeasured and the ramp-up or ramp-down procedure was resumed.

[0127] Subjects were again tested during Visit 7 according to the basicprocedures described above for Visit 5. This time, however, vagus nervestimulation given after the reading of half the paragraphs was for thesubjects in the Gamma Group at the tolerance intensity that each hadbeen ramped up to. This ranged from 0.75 mA to 1.5 mA. A final test wasconducted on Visit 9. This time, subjects in the Gamma Group receivedvagus nerve stimulation at their individual tolerance intensity (0.75 mAto 1.5 mA), while all subjects in the Delta Group received stimulationat 0.5 mA.

[0128] This experimental design enables each subject to establishhis/her own baseline against which stimulation effects are measured.Each stimulation group provided a standard of comparison to evaluate thegeneral effects of device implantation and vagus nerve stimulation onmemory performance. This is crucial as the pre-implantation baselinemeasures (Visit 4) rules out changes in performance merely resultingfrom surgery or the presence of the device. The pre-implantationbaseline is not in itself an adequate control for cognitive testingwithout an additional post-implantation stimulation baseline. Thiscontrol was provided by paragraph reading followed by no vagus nervestimulation in each group. Further, this experimental design permits thecomparison of the effects of different current intensity levels. Onehalf of the patients (those in the Gamma Group) were treated with 0.5 mAstimulation during Visit 5. The other half of the patients (the DeltaGroup) received no stimulation at either Visit 5 or Visit 7. On Visit 7,patients in the Gamma Group had their stimulation intensity increased totheir own individual tolerance level, not exceeding the ceilingintensity of 1.5 mA. Stimulation intensity is an important factor as theresults from laboratory animal studies (Clark et al. (1994) Society forNeuroscience Abstracts 20:802; Clark et al. (1995) Neurobiology ofLearning and Memory 63:213-216) indicate that this is an importantparameter. In that case, only 0.4 mA stimulation produced significantenhancement in retention performance. Lastly, if vagus nerve stimulationhas a capacity to improve memory or other cognitive functions in humans,it is most likely to do so for those specific events occurring during aninterval time-locked to the stimulus. The vagus nerve stimulationstimulus selectively enhances certain information over the milieu ofother information during the memory consolidation period. Generalneuropsychological tests for cognitive and memory performance are notdesigned to evaluate the time-locked pairing of salient cues (i.e.,vagus nerve stimulation-induced arousal) with the acquisition ofinformation. Therefore, any memory-modulating effect would be overlookedor masked (i.e., a lowered mean retention performance) by retentionqueries for acquired information other than that associated with ortime-locked to vagus nerve stimulation. The working memory paradigmdescribed above is, in contrast, sensitive to even subtle vagus nervestimulation influences on the formation of memories, since retention forwords time-locked to vagus nerve stimulation at three differentintensities are compared to retention for words time-locked to no vagusnerve stimulation.

[0129] Results

[0130] Recognition memory performance of eleven patients was analyzed intests performed on Visits 5, 7, and 9 (two, four, and sixteen weekspostimplantation, respectively). The results are summarized in FIGS. 1and 2.

[0131] Current Intensity at 0.5 mA

[0132]FIG. 1 shows the effect of vagus nerve stimulation (0.5 mA, 0.5 mspulse width, 30 Hz), given shortly after a learning experience,collapsed across Gamma- and Delta-group patients. To counterbalance fortime effects, patients (n=5) in the Gamma group received the abovementioned stimulus at Visit 5 while those patients (n=6) in Delta groupreceived the identical stimulation at Visit 9. Each subject read aseries of paragraphs, some of which contained highlighted words. In halfthe trials, reading a paragraph with highlighted words was followed byvagus nerve stimulation. In the other half of the trials, no stimulationwas given. Retention performance, measured as recognition of highlightedwords, showed that subjects remembered more words from trials that werefollowed by vagus nerve stimulation than they did in those trials inwhich no stimulation followed reading of the paragraphs (t(9)=2.78,p<0.025). These data indicate that regardless of the time after deviceimplantation, vagus nerve stimulation at 0.5 mA, when administered aftera learning experience, significantly enhanced retention performance ofthe learned material.

[0133] Current Intensity at Subject Tolerance

[0134] At Visits 7 and 9, patients in the Gamma group received vagusnerve stimulation at each individual's tolerance intensity (e.g., 0.75to 1.5 mA). FIG. 2 shows the effect of vagus nerve stimulation attolerance intensities for the Gamma group. Vagus nerve stimulation givenat tolerance intensities (0.75 to 1.5 mA) shortly after a learningexperience did not significantly enhance recognition performance(t(9)=0.76, p<0.470). This finding parallels those effects observed foranimals in the inventors' laboratory (Clark et al. (1994) Society forNeuroscience Abstracts 20:802; Clark et al. Neurobiology of Learning andMemory 63:213-216). Animals that received posttraining administration ofvagus nerve simulation showed significantly enhanced memory performanceat moderate current intensities (i.e. 0.4 mA), but not at thecomparatively higher stimulation intensity of 0.8 mA. Such aninput-output curve is analogous to the inverted U-shaped dose responsecurves commonly found for memory modulating drugs. Thus, these findingswith human subjects suggest that vagus nerve stimulation producesenhancement of memory storage processes in a manner similar to that ofother memory modulatory agents.

EXAMPLE 3 Treatment of Traumatic Brain Injury by Vagus Nerve Stimulation

[0135] Vagus nerve stimulation is expected to help sufferers oftraumatic brain injury in a number of ways.

[0136] First, vagus nerve stimulation induces increased neuronalactivity in widespread regions of the brain (Naritoku et al. (1995)Epilepsy Research 22:53-62). Such stimulation can ameliorate theproblems of brain hypometabolism and decrease in brain activity inducedby brain injury, and aid in improving recovery of cognition, motorskills, activities of daily living, and memory.

[0137] Secondly, vagus nerve stimulation activates the protein fos inbrain neurons (Naritoku et al., supra). Since this protein promotessubsequent transcription and translation of genes, thereby increasingthe production of cellular proteins, it enhances brain neural plasticityand thereby contributes to recovery from injury.

[0138] Thirdly, vagus nerve stimulation produces widespread increases ofmonoamines in the brain, including the neuro-transmitters serotonin andnorepinephrine. Several studies indicate that increases in monoaminesare antiepileptogenic, i.e, prevent epilepsy (Gellman et al. (1987) J.Pharmacol. Exp. Ther. 241:891-898). While drugs that increasemonoamines, such as amphetamines, cause undesired side effects, vagusnerve stimulation represents a means of increasing monoaminetransmission without negative side effects.

[0139] Next, vagus nerve stimulation will aid in preventing thedevelopment of epilepsy. Previous investigations on vagus nervestimulation have examined the treatment of established chronic epilepsy.The methods disclosed herein are expected to be useful in preventing thedevelopment of epilepsy itself. Several types of data support thishypothesis.

[0140] First, at least part of the anti-seizure properties of vagusnerve stimulation relates to activation of monoaminergic nuclei. Krahlet al. ((1994) Society for Neuroscience Abstracts 20:1453) havedemonstrated that inactivation of monoaminergic nuclei reduces theeffectiveness of vagus nerve stimulation. Furthermore, the data ofNaritoku et al. ((1995) Epilepsy Res. 22:53-62) demonstrate that vagusnerve stimulation activates the A5 and locus ceruleus noradrenergicnuclei.

[0141] Secondly, increasing monoaminergic transmission prevents thedevelopment of epilepsy in animals (Jobe et al. (1981) Biochem.Pharmacol. 30:3137-3144). This property has been termed“antiepileptogenic,” as opposed to “antiepileptic” or “anticonvulsant”.An antiepileptogenic therapy is distinctly different from antiepilepticor anticonvulsant therapies in that the latter two therapies preventseizures once epilepsy is established, but do not prevent thedevelopment of epilepsy, as do antiepilepto-genic therapies. The effectsof vagus nerve stimulation will prevent the processes that causeepilepsy. Specifically, injections of high amounts of monoaminergicdrugs such as clonidine block the rate at which epilepsy can beestablished in animal models using the kindling protocol, which involvesdirect applications of small amounts of electrical currents to limbicstructures (Burchfiel et al. (1989) Neurosci. Behav. Rev. 13:289-299;Gellman et al. (1987) J. Pharmacol. Exp. Ther. 241:891-898).

[0142] Thirdly, increases in serotonin or norepinephrine brought aboutby drugs such as fluoxetine reduce spontaneous and induced seizures inanimals and humans (Jobe et al. (1973) J. Pharmacol. Exp. Ther.184:1-10; Leander (1992) Epilepsia 33:573-576; Favale et al. (1995)Neurology 45:1926-1927).

[0143] Finally, vagus nerve stimulation is expected to improve memory inbrain-injured patients. As demonstrated in Example 1, supra, vagus nervestimulation improves memory function in normal human subjects.

[0144] Methods and Design

[0145] Types of Brain Injuries Amenable to Treatment by Vagus NerveStimulation

[0146] Vagus nerve stimulation can be used to improve recovery ofpatients suffering from traumatic brain injury such as that incurred,for example, from blows to the head from various objects; penetratinginjuries from missiles, bullets, shrapnel, etc., falls; skull fractureswith resulting penetration by bone pieces; sudden acceleration ordeceleration injuries; and other causes well known in the art. Exemplarysymptoms of such brain injuries include, but are not limited to,impaired level of consciousness, impaired cognition, impaired cognitiveprocessing speed, impaired language, impaired motor activity, impairedmemory, impaired motor skills, and impaired sensory skills.

[0147] Apparatus

[0148] The device and electrodes can be implanted as described in U.S.Pat. Nos. 5,154,172 and 5,269,303, although any conventional devicesknown in the art can be employed.

[0149] Stimulation Parameters of the Output Signal

[0150] The preferred range of stimulation parameters of the outputsignal of the stimulus generator for treatment of traumatic braininjury, and the typical value of each parameter of the output signalprogrammed into the device by the attending physician or therapist, canbe as follows.

[0151] The pulse width can be in the range of from about 50 μsec. toabout 1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec.,more preferably from about 250 μsec. to about 750 μsec., even morepreferably from about 400 μsec. to about 750 μsec., and most preferablyfrom about 400 μsec. to about 600 μsec. A pulse width of about 400 μsec.to about 750 μsec. is appropriate when C fiber activation is required ordesired. If only A and B fiber activation is required or desired, then apulse width of about 50 μsec. to about 250 μsec. would be effective. Thetype of fiber activation can vary between individual patients.

[0152] The output current can be in the range of from about 0.1 mA toabout 10 mA, more preferably from about 0.1 mA to about 6 mA, mostpreferably from about 0.1 mA to about 4mA.

[0153] The frequency of the output signal can be in the range of fromabout 1 Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz,most preferably from about 10 Hz to about 40 Hz.

[0154] The pulses can be monophasic, biphasic, or a combination thereof.

[0155] The train duration of the output current can be in the range offrom about 1 sec. to about 4 hours, more preferably from about 2.5 sec.to about 2.5 hours, most preferably from about 5 sec. to about 1 hour.The interval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand if this is determined to be preferable by thephysician or therapist.

[0156] The stimulating electrical signal can be applied to the vagusnerve any time after appearance of any of the symptoms noted above, forexample, within a time period of from about 1 hour to about 3 monthsafter appearance of the symptom.

[0157] Finally, the duration of the total therapy can vary dependingupon the nature and severity of the brain injury, as well as thephysical attributes and condition of the patient. Therapy can vary fromabout one day to as long as continued clinical improvement is obtainedor desired, e.g., several months or years to the remainder of thepatient's life. The necessity for, or desirability of, further therapycan be determined from results obtained via administering a variety ofdifferent clinical or laboratory tests to the patient. Examples ofuseful clinical tests include tests of activities required for dailyliving, memory, cognition, motor skills, development of epilepsy, FIM(Functional Index Measurement) scores, and other standardizedmeasurements of functional outcome. Examples of useful laboratory testsinclude a brain scan, a PET scan, a SPECT scan, an EEG, an evokedpotential, monitoring the level of a neurotransmitter such asnorepinephrine, serotonin, or dopamine, or metabolites thereof, in thebrain, and monitoring the level of a neurotransmitter in spinal fluid.

[0158] As will be recognized by those of ordinary skill in the art, anyor all of the foregoing vagus nerve stimulation parameters can betitrated clinically to achieve the desired response in a patient.

EXAMPLE 4

[0159] Prevention of Epilepsy by Vagus Nerve Stimulation

[0160] As noted above in Example 3, various types of data lead to theconclusion that vagus nerve stimulation is expected to be effective inpreventing the development of epilepsy. Such therapy is applicable notonly in the treatment of patients suffering from traumatic brain injury,but also in preventing the development of epilepsy in other subjectsprone to this disorder. This population includes patients predisposedto, or rendered susceptible to, developing epilepsy. These patientsinclude, for example, those suffering from a disease or condition suchas traumatic brain injury, post-encephalitic patients, post-strokepatients, and patients having a family history or genetic backgroundpredisposing them to developing epilepsy.

[0161] Methods and Design

[0162] Apparatus

[0163] The device and electrodes can be implanted as described in U.S.Pat. Nos. 5,154,172 and 5,269,303, although any conventional devicesknown in the art can be employed.

[0164] Stimulation Parameters of the Output Signal

[0165] The preferred range of stimulation parameters of the outputsignal of the stimulus generator for the prevention of epilepsy, and thetypical value of each parameter of the output signal programmed into thedevice by the attending physician or therapist, can be as follows.

[0166] The pulse width can be in the range of from about 50 μsec. toabout 1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec.,more preferably from about 250 μsec. to about 750 μsec., even morepreferably from about 400 μsec. to about 750 μsec., and most preferablyfrom about 400 μsec. to about 600 μsec. A pulse width of about 400 μsec.to about 750 μsec. is appropriate when C fiber activation is required ordesired. If only A and B fiber activation is required or desired, then apulse width of about 50 μsec. to about 250 μsec. would be effective. Thetype of fiber activation can vary between individual patients.

[0167] The output current can be in the range of from about 0.1 mA toabout 10 mA, more preferably from about 0.1 mA to about 6 mA, mostpreferably from about 0.1 mA to about 4 mA.

[0168] The frequency of the output signal can be in the range of fromabout 1 Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz,most preferably from about 10 Hz to about 40 Hz.

[0169] The pulses can be monophasic, biphasic, or a combination thereof.

[0170] The train duration of the output current can be in the range offrom about 1 sec. to about 4 hours, more preferably from about 2.5 sec.to about 2.5 hours, most preferably from about 5 sec. to about 1 hour.The interval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand if this is determined to be preferable by thephysician or therapist.

[0171] Finally, the duration of the total therapy can vary dependingupon the nature and severity of the underlying disorder or condition, aswell as the physical attributes and condition of the patient. Therapycan vary from about one day or one year to as long as continued clinicalimprovement is obtained or desired, e.g., several months or years to theremainder of the patient's life. In the case of preventing epilepsy, thetotal duration of therapy can be in the range of from about one day toas long as necessary to prevent development of epilepsy in the patient.Monitoring of patients for clinical improvement can be performed byconducting a procedure selected from an electroencephalogram, an evokedpotential, spectral mapping, voltage mapping, clinical assessment, andcombinations thereof.

[0172] As will be recognized by those of ordinary skill in the art, anyor all of the foregoing vagus nerve stimulation parameters can betitrated clinically to achieve the desired response in a patient.

EXAMPLE 5 Antiepileptogenic Effect of Vagus Nerve Stimulation in a RatElectrical Kindling Model

[0173] Electrical kindling is an important model of epileptogenesis,i.e., the development of a chronic seizure focus. Since repeatedkindling sessions cause progressive increases in severe seizure severity(Goddard et al. (1969) Exp. Neurol. 25:295-330), electrical kindling canbe utilized to test for antiepileptogenic properties of a given therapy(Schmutz et al. (1988) J. Neural. Transm. 72:245-257; Silver et al.(1991) Ann. Neurol. 29:356-363). The effectiveness of vagus nervestimulation in opposing epileptogenesis was therefore investigated usingthis paradigm.

[0174] Experimental

[0175] Electrodes were implanted on the left vagus nerve of adult maleSprague-Dawley rats (250-300 g) to provide vagus nerve stimulation. Atwisted pair depth electrode was implanted into the right amygdala(coordinates from bregma: AP −2.4 mm; ventral −8.6m; lateral −4.2 mm)using a stereotaxic device, and the animals were allowed to recuperatefor at least one week.

[0176] On the first day, the kindling threshold was determined byapplying 100 Hz biphasic square wave pulses to the depth electrode for30 sec. The current was increased in 10 μA increments until at least a10 sec. aferdischarge was obtained. The resulting threshold current wasrecorded for each animal and used for subsequent sessions. Prior to eachkindling session, vagus nerve stimulation (1 mA/30 Hz/500 μsec. biphasicsquare pulses) or sham stimulation (i.e., identical handling, no vagusnerve stimulation) was administered for one hour. Subsequently, dailykindling stimuli were administered through the depth electrode (biphasicsquare wave, 100 Hz). Seizures were scored on a standard severity scale(Racine, R. J. (1972) Electroencephalogr. Clin. Neurophysiol. 32:281) ona scale from 0 to 5, in which 5 represents a fully kindled convulsiveseizure. The results are shown in FIG. 4.

[0177] Results

[0178] As can be seen in FIG. 4, there were significant differences inthe progression of kindling stage for rats that received vagus nervestimulation pretreatment (-▪-, n=4), control animals that did notreceive vagus nerve stimulation

[0179] (--, n=5), and a third comparison group (-▴-, n=7) that receivedvagus nerve stimulation for the first 6 days, but not for subsequentkindling sessions (p=0.0001; repeated measures ANOVA).

[0180] Post-hoc analysis revealed that there was a significant delay inanimals that received vagus nerve stimulation compared to controlanimals (p≦0.01; Newman-Keuls test). The mean stimuli to class 5seizures was 11.3±1.5 (days±SD) in vagus nerve stimulation-treatedanimals (-▪-) compared to 6.0±1.2 in sham-treated animals (--; p=0.001;t-test).

[0181] To assure that the treatment opposed epileptogenesis rather thanmasking the resulting seizure, the third group received vagus nervestimulation for 6 kindling sessions, and then received no vagus nervestimulation during subsequent sessions. This is shown by the middlecurve (-▴-) in FIG. 4. As expected, the rate of kindling in this groupwas similar to that in the other treated group that received the firstsix vagus nerve stimulations (-▪-). If vagus nerve stimulation wassimply masking the seizure severity, the severity score would beexpected to increase to control values for the remaining kindlingsessions. However, the seizure severity scores remained significantlylower than those in control animals (p≦0.01, Neuman-Keuls test), andexhibited an intermediate progression of severity increases. Theseresults demonstrate that the vagus nerve stimulation opposed, ratherthan masked, epileptogenesis.

[0182] In summary, these kindling experiments indicate that vagus nervestimulation can oppose epileptogenesis, and may therefore be a usefultherapy to prevent the development of epilepsy in clinical situationsassociated with a high risk for developing epilepsy.

EXAMPLE 6 Treatment of Memory Disorders and Chronic Memory Impairment byVagus Nerve Stimulation

[0183] Electrical stimulation of the vagus nerve can also be used intherapies to treat subjects suffering from diseases or conditions inwhich memory impairment or learning disorders are a prominent feature.Examples of such diseases or conditions include Alzheimer's Disease,Binswanger Disease, Pick's Disease, Parkinson's Disease, cerebral palsy,post-meningitis, post-encephalitis, traumatic brain injury,Wernicke-Korsakoff syndrome, alcohol-related memory disorders,post-temporal lobectomy, memory loss from multi-infarct (stroke) state,multiple sclerosis, post-cardiac arrest injury, post-hypoxic injury, andnear drowning.

[0184] Electrical stimulation of the vagus nerve can also be used intherapies to treat subjects suffering from disorders in which impairmentof cognitive processing speed, acquisition of perceptual skills,acquisition of motor skills, or perceptual processing are a prominentfeature. Examples of these diseases or conditions include mentalretardation, multiple sclerosis, perinatal asphyxia, intrauterineinfections, cerebral palsy, post-meningitis, post-encephalitis,dyslexia, constructional apraxia, post-cardiac arrest injury,post-hypoxic injury, multi-infarct (stroke) state, and near drowning.

[0185] Methods and Design

[0186] Apparatus

[0187] The device and electrodes can be implanted as described in U.S.Pat. Nos. 5,154,172 and 5,269,303, although any conventional devicesknown in the art can be employed.

[0188] Stimulation Parameters of the Output Signal

[0189] The preferred range of stimulation parameters of the outputsignal of the stimulus generator for the treatment of memory impairment,learning disorders, impairment of cognitive processing speed,acquisition of perceptual skills, acquisition of motor skills, orperceptual processing, and the typical value of each parameter of theoutput signal programmed into the device by the attending physician ortherapist, can be as follows.

[0190] The pulse width can be in the range of from about 50 μsec. toabout 1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec.,more preferably from about 250 μsec. to about 750 μsec., even morepreferably from about 400 μsec. to about 750 μsec., and most preferablyfrom about 400 μsec. to about 600 μsec. A pulse width of about 400 μsec.to about 750 μsec. is appropriate when C fiber activation is required ordesired. If only A and B fiber activation is required or desired, then apulse width of about 50 μsec. to about 250 μsec. would be effective. Thetype of fiber activation can vary between individual patients.

[0191] The output current can be in the range of from about 0.1 mA toabout 10 mA, more preferably from about 0.1 mA to about 6 mA, mostpreferably from about 0.1 mA to about 4 mA.

[0192] The frequency of the output signal can be in the range of fromabout 1 Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz,most preferably from about 10 Hz to about 40 Hz.

[0193] The pulses can be monophasic, biphasic, or a combination thereof.

[0194] The train duration of the output current can be in the range offrom about 1 sec. to about 4 hours, more preferably from about 2.5 sec.to about 2.5 hours, most preferably from about 5 sec. to about 1 hour.The interval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand if this is determined to be preferable by thephysician or therapist.

[0195] The stimulating electrical current can be applied to the vagusnerve any time after appearance of the symptom(s) to be treated.

[0196] Finally, the duration of the total therapy can vary dependingupon the nature and severity of the disorder, condition, or impairment,as well as the physical attributes and condition of the patient. Therapycan vary from about one day to as long as continued clinical improvementis obtained or desired, e.g., several months or years to the remainderof the patient's life. Clinical tests that can be employed to monitorthe success of therapy include standard neuropsychological tests such asWISC, WAIS, Halsted-Reitan, and combinations thereof. Useful laboratorytests include, for example, electroencephalograms, evoked potentials,spectral mapping, voltage mapping, clinical assessment, and combinationsthereof.

[0197] As will be recognized by those of ordinary skill in the art, anyor all of the foregoing vagus nerve stimulation parameters can betitrated clinically to achieve the desired response in a patient.

EXAMPLE 7 Treatment of Persistent Impairment of Consciousness by VagusNerve Stimulation

[0198] The present inventors have also concluded that vagus nervestimulation can be employed in the treatment of persistent impairment ofconsciousness, such as that associated with coma or vegetative states.

[0199] Methods and Design

[0200] Apparatus

[0201] The device and electrodes can be implanted as described in U.S.Pat. Nos. 5,154,172 and 5,269,303, although any conventional devicesknown in the art can be employed.

[0202] Stimulation Parameters of the Output Signal

[0203] The preferred range of stimulation parameters of the outputsignal of the stimulus generator for the treatment of persistentimpairment of consciousness, and the typical value of each parameter ofthe output signal programmed into the device by the attending physicianor therapist, can be as follows.

[0204] The pulse width can be in the range of from about 50 μsec. toabout 1,500 μsec., preferably from about 100 μsec. to about 1,000 μsec.,more preferably from about 250 μsec. to about 750 μsec., even morepreferably from about 400 μsec. to about 750 μsec., and most preferablyfrom about 400 μsec. to about 600 μsec. A pulse width of about 400 μsec.to about 750 μsec. is appropriate when C fiber activation is required ordesired. If only A and B fiber activation is required or desired, then apulse width of about 50 μsec. to about 250 μsec. would be effective. Thetype of fiber activation can vary between individual patients.

[0205] The output current can be in the range of from about 0.1 mA toabout 10 mA, more preferably from about 0.1 mA to about 6 mA, mostpreferably from about 0.1 mA to about 4 mA.

[0206] The frequency of the output signal can be in the range of fromabout 1 Hz to about 75 Hz, more preferably about 5 Hz to about 60 Hz,most preferably from about 10 Hz to about 40 Hz.

[0207] The pulses can be monophasic, biphasic, or a combination thereof.

[0208] The train duration of the output current can be in the range offrom about 1 sec. to about 4 hours, more preferably from about 2.5 sec.to about 2.5 hours, most preferably from about 5 sec. to about 1 hour.The interval between trains can be in the range of from about 1 sec. toabout 1 week, more preferably from about 1 sec. to about 1 day, mostpreferably from about 5 sec. to about 4 hours. Trains can also besupplied on demand if this is determined to be preferable by thephysician or therapist.

[0209] The stimulating electrical current can be applied to the vagusnerve any time after appearance of symptoms associated with persistentimpairment of consciousness, for example within a time period of fromabout one hour to about three months after appeance of such symptoms.

[0210] Finally, the duration of the total therapy can vary dependingupon the nature and severity of the impairment, as well as the physicalattributes and condition of the patient. Therapy can vary from about oneday to as long as continued clinical improvement is obtained or desired,e.g., several months or years to the remainder of the patient's life.

[0211] As will be recognized by those of ordinary skill in the art, anyor all of the foregoing vagus nerve stimulation parameters can betitrated clinically to achieve the desired response in a patient.

[0212] The invention being thus described, it will be obvious that thesame can be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the present invention, andall such modifications as would be obvious to one skilled in the art areintended to be included within the scope of the following claims.

What is claimed is:
 1. A method of treating a human or animal subjectsuffering from persistent impairment of consciousness, the methodcomprising: (a) selecting a human or animal subject suffering frompersistent impairment of consciousness; (b) applying to the vagus nerveof said human or animal subject a stimulating electrical signal, saidelectrical signal being effective to alleviate said persistentimpairment of consciousness; (c) monitoring said human or animal subjectto determine if said persistent impairment of consciousness has beenalleviated, or if further stimulation of said vagus nerve is required toalleviate said persistent impairment of consciousness; and (d) ifrequired, further stimulating said vagus nerve and monitoring said humanor animal subject as in preceding steps (b) and (c), respectively, untilsaid persistent impairment of consciousness has been alleviated.
 2. Amethod as set forth in claim 1 further comprising producing saidstimulating electrical signal with a stimulus generator implanted withinsaid human or animal subject's body.
 3. A method as set forth in claim 1wherein the electrical signal supplies a current to the vagus nerve inthe range of from about 0.1 mA to about 10 mA.
 4. A method as set forthin claim 1 wherein the electrical signal supplies a current to the vagusnerve in the range of from about 0.1 mA to about 4 mA.
 5. A method asset forth in claim 1 wherein the electrical signal comprises a train ofpulses, each pulse having a pulse width ranging from about 50 μsec. toabout 1,500 μsec.
 6. A method as set forth in claim 1 wherein theelectrical signal comprises a train of pulses, each pulse having a pulsewidth ranging from about 400 μsec. to about 750 μsec.
 7. A method as setforth in claim 1 wherein the electrical signal comprises a train ofpulses having a frequency ranging from about 1 Hz to about 75 Hz.
 8. Amethod as set forth in claim 1 wherein the electrical signal comprises atrain of pulses having a frequency ranging from about 10 Hz to about 40Hz.
 9. A method as set forth in claim 1 wherein the electrical signal ismonophasic, biphasic, or a combination thereof.
 10. A method as setforth in claim 1 wherein the electrical signal comprises a train ofpulses having a train duration ranging from about 1 second to about 4hours.
 11. A method as set forth in claim 1 wherein the electricalsignal comprises a train of pulses having a train duration ranging fromabout 5 seconds to about 1 hour.
 12. A method as set forth in claim 1wherein the electrical signal comprises trains of pulses having aninterval between trains ranging from about 1 second to about 1 week. 13.A method of as set forth in claim 1 wherein the electrical signalcomprises trains of pulses having an interval between trains rangingfrom about 5 seconds to about 4 hours.
 14. A method as set forth inclaim 10 wherein trains are supplied on demand.
 15. A method as setforth in claim 1, wherein said monitoring of step (c) is performed via amember selected from the group consisting of clinical outcome, aclinical test, a laboratory test, and combinations thereof.
 16. A methodas set forth in claim 15, wherein said laboratory test is selected fromthe group consisting of a brain scan, a PET scan, a SPECT scan, an EEG,an evoked potential, monitoring the level of a neurotransmitter in thebrain, and monitoring the level of a neurotransmitter in spinal fluid.